title: Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871).
abstract: Figitumumab (CP-751,871), a potent and fully human monoclonal anti-insulin-like growth factor 1 receptor (IGF1R) antibody, has been investigated in clinical trials of several solid tumors. To identify biomarkers of sensitivity and resistance to figitumumab, its in vitro antiproliferative activity was analyzed in a panel of 93 cancer cell lines by combining in vitro screens with extensive molecular profiling of genomic aberrations. Overall response was bimodal and the majority of cell lines were resistant to figitumumab. Nine of 15 sensitive cell lines were derived from colon cancers. Correlations between genomic characteristics of cancer cell lines with figitumumab antiproliferative activity revealed that components of the IGF pathway, including IRS2 (insulin receptor substrate 2) and IGFBP5 (IGF-binding protein 5), played a pivotal role in determining the sensitivity of tumors to single-agent figitumumab. Tissue-specific differences among the top predictive genes highlight the need for tumor-specific patient selection strategies. For the first time, we report that alteration or expression of the MYB oncogene is associated with sensitivity to IGF1R inhibitors. MYB is dysregulated in hematologic and epithelial tumors, and IGF1R inhibition may represent a novel therapeutic opportunity. Although growth inhibitory activity with single-agent figitumumab was relatively rare, nine combinations comprising figitumumab plus chemotherapeutic agents or other targeted agents exhibited properties of synergy. Inhibitors of the ERBB family were frequently synergistic and potential biomarkers of drug synergy were identified. Several biomarkers of antiproliferative activity of figitumumab both alone and in combination with other therapies may inform the design of clinical trials evaluating IGF1R inhibitors.
authors.affiliation: Corresponding Author: James G. Christensen, Mirati Therapeutics, 9363 Towne Center Drive, Suite 200, San Diego, CA 92121. christensenj@mirati.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.forename: Maruja E
authors.initials: ME
authors.lastname: Lira
authors.forename: Nathan V
authors.initials: NV
authors.lastname: Lee
authors.forename: Keith A
authors.initials: KA
authors.lastname: Ching
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Garza
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hook
authors.forename: Mark
authors.initials: M
authors.lastname: Ozeck
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: Julie L C
authors.initials: JL
authors.lastname: Kan
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D040641:Quantitative Trait Loci; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1; C525021:figitumumab